The susceptibility of diabetic animals to macrovascular disease will be studied in streptozotocin-treated rats and alloxan-treated rabbits subjected to balloon injury of the aortic endothelium. The morphologic response of the arterial wall to injury will be studied by light and electron microscopy and will be correlated with the chemical and biochemical alterations which develop. Endothelial permeability, cell proliferation, and connective tissue and lipid metabolism will be assessed in these models. Studies will also be carried out in obese hyperinsulinemic rats and in animals with chemically-induced diabetes treated with insulin in order to assess the role of insulin on the arterial response to injury. In addition, the influence of plasma lipoprotein concentrations will be examined both with and without cholesterol feeding in the control and diabetic animals. The studies will also be concerned with the regulation of cholesterol metabolism in the arterial wall. The properties of the aortic lysosomal lipase will be studied in detail and the hydrolysis of labeled lipoproteins and artificial substrates by normal and atherosclerotic tissue will be examined. Non-lysosomal cholesterol esterase activity in aorta will be assessed, particularly with respect to potential hormone-sensitivity. Studies will be continued regarding the factors which regulate fatty acyl CoA: cholesteryl acyl transferase (ACAT) activity in the vessel wall. Finally, the interaction between lipoproteins and artificial or natural membranes will be examined in relation to lipoprotein catabolism and cholesterol mobilization.